Process and crystalline forms of lumacaftor

ABSTRACT

The present invention generally relates to crystalline forms of Lumacaftor, processes for its preparation and pharmaceutical compositions thereof. The present invention also relates to an improved process for preparation of Lumacaftor.

PRIORITY

This application claims the benefit under Indian Provisional ApplicationNo. 201741000812 filed on 9 Jan. 2017 entitled “Process and crystallineforms of lumacaftor”, the contents of which is incorporated by referenceherein.

FIELD OF THE INVENTION

The present invention generally relates to crystalline forms ofLumacaftor, processes for its preparation and pharmaceuticalcompositions thereof. The present invention also relates to an improvedprocess for the preparation of Lumacaftor.

BACKGROUND OF THE INVENTION

3-{6-{[1-(2,2-Difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino}-3-methylpyridine-2-yl}benzoic acid, commonly known as Lumacaftor having thecompound of Formula I, is a modulator of CFTR activity and thus usefulin treating CFTR-mediated diseases such as cystic fibrosis (CF).

Cystic Fibrosis (CF) is a fatal autosomal recessive disease associatedwith defective hydration of lung airways due to the loss of function ofthe CF transmembrane conductance regulator (CFTR) channel at epithelialcell surfaces.

In patients with CF, mutations in CFTR endogenously expressed inrespiratory epithelia leads to reduced apical anion secretion causing animbalance in ion and fluid transport. The resulting decrease in aniontransport contributes to enhanced mucus accumulation in the lung and theaccompanying microbial infections that ultimately cause death in CFpatients. In addition to respiratory disease, CF patients typicallysuffer from gastrointestinal problems and pancreatic insufficiency that,if left untreated, results in death. In addition, the majority of maleswith cystic fibrosis are infertile and fertility is decreased amongfemales with cystic fibrosis. In contrast to the severe effects of twocopies of the CF associated gene, individuals with a single copy of theCF associated gene exhibit increased resistance to cholera and todehydration resulting from diarrhea—perhaps explaining the relativelyhigh frequency of the CF gene within the population. Lumacaftor has beendemonstrated to restore the function of the cystic fibrosistransmembrane conductance regulator (CFTR) protein.

Lumacaftor is available in a single pill with Ivacaftor combination,lumacaftor/ivacaftor having the brand name Orkambi®, is used to treatpeople with cystic fibrosis who have the F508del mutation in the cysticfibrosis transmembrane conductance regulator (CFTR). Lumacaftor wasdeveloped by Vertex Pharmaceuticals and the Lumacaftor/Ivacaftorcombination was approved by the FDA in 2015.

PCT publication No. 2007/056341 (“the '341 publication”) disclosesmodulators of ATP-Binding Cassette (“ABC”) transporters including CysticFibrosis Transmembrane conductance Regulator (“CFTR”) such aslumacaftor. The '341 publication discloses a process for preparation oflumacaftor by reaction of Formula II (chloro intermediate) with FormulaIII by microwave irradiation at a temperature of about 150° C. to obtainlumacaftor, which is purified by reverse-phase preparative liquidchromatography. The process disclosed in the '341 publication isschematically represented as follows:

The synthesis of lumacaftor as disclosed in the '341 publication hascertain drawbacks as it involves:

-   -   a) reaction of Formula II (chloro intermediate) with Formula III        involves microwave irradiation at 150° C. The use of special        techniques such as reaction by microwave irradiation is not        viable for commercial scale operations as this technique        involves specialized expensive equipment's, and    -   b) involves tedious reverse-phase preparative liquid        chromatography purifications, which contributes significant        impact on the final yield and purity, makes the process not        viable for large scale manufacturing.

PCT Publication No. 2009/073757 (“the '757 publication”) disclosedcrystalline Form I of lumacaftor. The '757 publication also disclosesalternative process for preparation of lumacaftor. The '757 publicationexemplified process involves lengthy process like using esterintermediate as starting material and followed by hydrolysis of theester group at final step to obtain lumacaftor. The process disclosed inthe '757 publication is schematically represented as follows:

PCT Publication No. 2011/127290 (“the '290 publication”) disclosedcrystalline Form A of lumacaftor hydrochloride salt and furtherdisclosed various isostructural solvates of lumacaftor such as methanolsolvate, ethanol solvate, acetone solvate, 2-propanol solvate,acetonitrile solvate, tetrahydrofuran solvate, methyl acetate solvate,2-butanone solvate, ethyl formate solvate and 2-methyl tetrahydrofuransolvate and process for their preparation, wherein the process forpreparing isostructural solvates involves the slurring of solvatereaction mixture for 48 hours.

Indian Publication No.(s) 201641000118, 201621004780 & 5209/CHE/2015disclosed process for preparation of amorphous form of lumacaftor.

CN Publication No. 106432209 disclosed preparation of crystalline form Aof lumacaftor from methyl isobutyl ketone and a mixture of methylisobutyl ketone and acetone.

PCT Publication No. 2017/017696 (“the '696 publication”) disclosedpreparation of lumacaftor. The process disclosed in the '696 publicationis schematically represented as follows:

PCT Publication No. 2017/056031 (“the '031 publication”) disclosedpreparation of lumacaftor. The process disclosed in the '031 publicationis schematically represented as follows:

PCT Publication No. 2017/175161 (“the '161 publication”) disclosedpreparation of lumacaftor. The '161 publication also disclosedhydrobromide salt of lumacaftor, crystalline form SV1-SV4 of lumacaftorand its process for preparation thereof. The process disclosed in the'161 publication is schematically represented as follows:

PCT Publication No. 2017/118915 (“the '915 publication”) disclosedamorphous form of lumacaftor and its process for preparation thereof.Further, the '915 publication disclosed crystalline complex oflumacaftor and ivacaftor and its process for preparation thereof.

PCT Publication No. 2017/137900 (“the '900 publication”) disclosedamorphous form of lumacaftor and its process for preparation thereof.Further, the '900 publication disclosed crystalline form A of lumacaftorhydrobromide salt.

PCT Publication No. 2017/025045 (“the '045 publication”) disclosedcrystalline form A of lumacaftor and its process for preparationthereof.

Polymorphism is the occurrence of different crystalline forms of asingle compound and it is a property of some compounds and complexes.Thus, polymorphs are distinct solids sharing the same molecular formula,yet each polymorph may have distinct physical properties. Therefore, asingle compound may give rise to a variety of polymorphic forms whereeach form has different and distinct physical properties, such asdifferent solubility profiles, different melting point temperaturesand/or different x-ray diffraction peaks. Since the solubility of eachpolymorph may vary, identifying the existence of pharmaceuticalpolymorphs is essential for providing pharmaceuticals with predicablesolubility profiles. It is desirable to investigate all solid stateforms of a drug, including all polymorphic forms and solvates, and todetermine the stability, dissolution and flow properties of eachpolymorphic form. Polymorphic forms and solvates of a compound can bedistinguished in a laboratory by X-ray diffraction spectroscopy and byother methods such as, infrared spectrometry. Additionally, polymorphicforms and solvates of the same drug substance or active pharmaceuticalingredient, can be administered by itself or formulated as a drugproduct (also known as the final or finished dosage form), and are wellknown in the pharmaceutical art to affect, for example, the solubility,stability, flowability, tractability and compressibility of drugsubstances and the safety and efficacy of drug products.

The discovery of new crystalline polymorphic forms and solvates of apharmaceutically useful compound, like lumacaftor, may provide a newopportunity to improve the performance characteristics of apharmaceutical product. It also adds to the material that a formulationscientist has available for designing, for example, a pharmaceuticaldosage form of a drug with a targeted release profile or other desiredcharacteristic. New crystalline polymorphic forms of the lumacaftor havenow been discovered and have been designated as Form LA1, Form LA2 andForm LA3.

Based on the process drawbacks mentioned in the '341 and '757publications, there is a vital need to develop a process for thepreparation of lumacaftor, which is readily amenable to large scaleproduction.

Hence, present inventors focused research to simplify the process forthe preparation of lumacaftor, which avoids mainly microwave irradiationthereby avoiding the formation of impurities and making the process moresuitable for commercial applications with higher purity and obviate theproblems associated with the reported processes.

SUMMARY OF THE INVENTION

The present invention provides novel crystalline forms of lumacaftor,process for their preparation and pharmaceutical compositions comprisingone or more of the novel crystalline forms of lumacaftor. The presentinvention also relates to an improved process for preparation oflumacaftor.

In accordance with one embodiment, the present invention provides novelcrystalline forms of lumacaftor.

In accordance with another embodiment, the present invention providesnovel crystalline forms of lumacaftor, herein designated as lumacaftorForm-LA1, lumacaftor Form-LA2 and lumacaftor Form-LA3.

In accordance with another embodiment, the lumacaftor Form-LA1 of thepresent invention is an anhydrous crystalline from.

In accordance with another embodiment, the present invention providescrystalline lumacaftor Form-LA1 characterized by a X-ray powderdiffraction in accordance with FIG. 1.

In accordance with another embodiment, the present invention providescrystalline lumacaftor Form-LA1 characterized by a differential scanningcalorimetry (DSC) thermogram substantially in accordance with FIG. 2.

In accordance with another embodiment, the present invention providescrystalline lumacaftor Form-LA1 characterized by a thermo gravimetricanalysis (TGA) curve substantially in accordance with FIG. 3.

In accordance with another embodiment, the present invention providescrystalline lumacaftor Form-LA1, characterized by a powder X-Raydiffraction (PXRD) pattern substantially in accordance with FIG. 1, adifferential scanning calorimetry (DSC) substantially in accordance withFIG. 2 and a thermo gravimetric analysis (TGA) substantially inaccordance with FIG. 3.

In accordance with another embodiment, the present invention provides aprocess for the preparation of lumacaftor Form-LA1, comprising:

-   -   a) dissolving lumacaftor in water and a suitable base at a        suitable temperature,    -   b) optionally, cooling the solution to less than 25° C., and    -   c) isolating the lumacaftor Form-LA1.

In accordance with another embodiment, the present invention provides aprocess for the preparation of lumacaftor Form-LA1, comprising:

-   -   a) dissolving lumacaftor in water and a suitable base at a        suitable temperature,    -   b) optionally, cooling the solution to less than 25° C., and    -   c) isolating the lumacaftor Form-LA1; wherein the suitable base        is selected from the group comprising ammonium bases, alkali        metal hydroxides, alkali metal alkoxides, alkali metal        carbonates, alkali metal bicarbonates or organic bases and        mixture thereof.

In accordance with another embodiment, the present invention provides aprocess for the preparation of lumacaftor Form-LA1, comprising:

-   -   a) dissolving lumacaftor in water and a suitable base at a        temperature of about 35° C. to about reflux temperature,    -   b) optionally, cooling the solution to less than 25° C., and    -   c) isolating the lumacaftor Form-LA1; wherein the suitable base        is selected from the group comprising ammonium bases, alkali        metal hydroxides, alkali metal alkoxides, alkali metal        carbonates, alkali metal bicarbonates or organic bases and        mixture thereof.

In accordance with another embodiment, the present invention provides aprocess for the preparation of lumacaftor Form-LA1, comprising:

-   -   a) dissolving lumacaftor in water and ammonium hydroxide at a        temperature of about 35° C. to reflux temperature,    -   b) optionally, cooling the solution to less than 25° C., and    -   c) isolating the lumacaftor Form-LA1.

In accordance with another embodiment, the present invention provides aprocess for the preparation of lumacaftor Form-LA1, comprising:

-   -   a) suspending lumacaftor in water,    -   b) adding ammonium hydroxide to the step a) suspension or        vice-versa,    -   c) heating the step b) reaction mixture to about 35° C. to        reflux temperature,    -   d) cooling the step c) reaction mixture to less than 25° C., and    -   e) isolating the lumacaftor Form-LA1.

In accordance with another embodiment, the lumacaftor Form-LA2 of thepresent invention is an ammonia solvate.

In accordance with another embodiment, the present invention providescrystalline lumacaftor Form-LA2 characterized by a X-ray powderdiffraction in accordance with FIG. 4.

In accordance with another embodiment, the present invention providescrystalline lumacaftor Form-LA2 characterized by a differential scanningcalorimetry (DSC) thermogram substantially in accordance with FIG. 5.

In accordance with another embodiment, the present invention providescrystalline lumacaftor Form-LA2 characterized by a thermo gravimetricanalysis (TGA) curve substantially in accordance with FIG. 6.

In accordance with another embodiment, the present invention providescrystalline lumacaftor Form-LA2, characterized by a powder X-Raydiffraction (PXRD) pattern substantially in accordance with FIG. 4, adifferential scanning calorimetry (DSC) substantially in accordance withFIG. 5 and a thermo gravimetric analysis (TGA) substantially inaccordance with FIG. 6.

In accordance with another embodiment, the present invention provides aprocess for the preparation of lumacaftor Form-LA2, comprising: exposinglumacaftor Form-LA1 under ammonia atmosphere.

In accordance with another embodiment, the lumacaftor Form-LA3 of thepresent invention is an anhydrous crystalline from.

In accordance with another embodiment, the present invention providescrystalline lumacaftor Form-LA3 characterized by a X-ray powderdiffraction in accordance with FIG. 7.

In accordance with another embodiment, the present invention providescrystalline lumacaftor Form-LA3 characterized by a differential scanningcalorimetry (DSC) thermogram substantially in accordance with FIG. 8.

In accordance with another embodiment, the present invention providescrystalline lumacaftor Form-LA3 characterized by a thermo gravimetricanalysis (TGA) curve substantially in accordance with FIG. 9.

In accordance with another embodiment, the present invention providescrystalline lumacaftor Form-LA3, characterized by a powder X-Raydiffraction (PXRD) pattern substantially in accordance with FIG. 7, adifferential scanning calorimetry (DSC) substantially in accordance withFIG. 8 and a thermo gravimetric analysis (TGA) substantially inaccordance with FIG. 9.

In accordance with another embodiment, the present invention provides aprocess for the preparation of lumacaftor Form-LA3, comprising: heatinglumacaftor Form-LA1 at about 100° C. to about 140° C. for about 3 to 12hours.

In accordance with another embodiment, the present invention provides animproved process for the preparation of lumacaftor with high productyield and quality, wherein the improvements comprise use of conventionalsynthesis, which avoids cumbersome microwave irradiation, therebyavoiding the formation of impurities.

In accordance with another embodiment, the present invention provides animproved process for the preparation of lumacaftor of Formula I,

comprising: reacting a compound of Formula II; wherein ‘X’ represent asuitable leaving group, with a compound of Formula III in presence of apalladium catalyst and base in a suitable solvent to obtain lumacaftor.

In accordance with another embodiment, the present invention provides aprocess for the preparation of lumacaftor Form-LA1, comprising:

-   -   a) reacting a compound of Formula II; wherein ‘X’ represent a        suitable leaving group, with a compound of Formula III in        presence of a palladium catalyst and base in a suitable solvent        to obtain lumacaftor,    -   b) dissolving lumacaftor from step a) in water and a suitable        base at a suitable temperature,    -   c) optionally, cooling the solution to less than 25° C., and    -   d) isolating the lumacaftor Form-LA1.

In accordance with another embodiment, the present invention providesthe use of novel crystalline forms of lumacaftor Form-LA1, Form-LA2 orForm-LA3 as an intermediate to prepare other polymorphic forms oflumacaftor.

In accordance with another embodiment, the present invention provides aprocess for the preparation of lumacaftor Form I, comprising:

-   -   a) suspending lumacaftor Form-LA1 in a suitable solvent; and    -   b) isolating the lumacaftor Form I.

In accordance with another embodiment, the present invention provides apharmaceutical composition comprising lumacaftor or a combination oflumacaftor and Ivacaftor, prepared by the process of the presentinvention and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate several embodiments of theinvention and together with the description, serve to explain theprinciples of the invention.

FIG. 1 is the characteristic powder X-ray diffraction (XRD) pattern oflumacaftor Form-LA1.

FIG. 2 is the characteristic differential scanning calorimetric (DSC)thermogram of lumacaftor Form-LA1.

FIG. 3 is the characteristic thermo gravimetric analysis (TGA)thermogram of lumacaftor Form-LA1.

FIG. 4 is the characteristic powder X-ray diffraction (XRD) pattern oflumacaftor Form-LA2.

FIG. 5 is the characteristic differential scanning calorimetric (DSC)thermogram of lumacaftor Form-LA2.

FIG. 6 is the characteristic thermo gravimetric analysis (TGA)thermogram of lumacaftor Form-LA2.

FIG. 7 is the characteristic powder X-ray diffraction (XRD) pattern oflumacaftor Form-LA3.

FIG. 8 is the characteristic differential scanning calorimetric (DSC)thermogram of lumacaftor Form-LA3.

FIG. 9 is the characteristic thermo gravimetric analysis (TGA)thermogram of lumacaftor Form-LA3.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise specified in this specification, “solvate” herein usedin this specification, refers to a crystals form that incorporates asolvent in the crystal structure. The solvent in a solvate may bepresent in either a stoichiometric or in a non-stoichiometric amount.

The present invention provides novel crystalline forms of lumacaftor,process for their preparation and pharmaceutical compositions comprisingone or more of the novel crystalline forms of lumacaftor. The presentinvention also relates to an improved process for preparation oflumacaftor.

As used herein, unless otherwise specified, lumacaftor, which is used asa starting material is known in the art and can be prepared by theprocess described in the present specification or may be any methodsknown in art. The starting lumacaftor may be in any form such as crudeobtained directly from the reaction mass, crystalline, amorphous orother forms of lumacaftor, including various solvates and hydrates knownin the art as well as the novel crystalline forms described herein thepresent invention.

In another embodiment, the present invention provides novel crystallineforms of lumacaftor, which are characterized by one or more ofanalytical techniques such as powder X-Ray diffraction (XRD),differential scanning calorimetry (DSC) and/or thermo gravimetricanalysis (TGA).

The X-Ray powder diffraction can be measured using PANalytical X′per³proX-ray powder Diffractometer equipped with a Cu-anode ([k]=1.54Angstrom), X-ray source operated at 45 kV, 40 mA. Two-theta calibrationis performed using an NIST SRM 640c Si standard. The sample was analyzedusing the following instrument parameters: measuring range=3-45° 20;step size=0.01°; and Time per step=50 sec.

All DSC data reported herein were analyzed in hermitically sealedaluminium pan, with an empty hermitically sealed aluminium pan as thereference and were obtained using DSC (DSC Q200, TA instrumentation,Waters) at a scan rate of 10° C. per minute in the range of 50 to 250°C.

All TGA data reported herein were analyzed using TGA Q500 in platinumpan with a temperature rise of about 10° C./min in the range of aboutroom temperature to about 250° C.

In another embodiment, the present invention provides novel crystallineforms of lumacaftor, herein designated as lumacaftor Form-LA1,lumacaftor Form-LA2 and lumacaftor Form-LA3.

In another embodiment, the lumacaftor Form-LA1 of the present inventionis an anhydrous crystalline from.

In another embodiment, the present invention provides lumacaftorForm-LA1 characterized by a powder X-ray diffraction (PXRD) patternsubstantially in accordance with FIG. 1.

In another embodiment, the present invention provides lumacaftorForm-LA1 characterized by X-Ray diffraction (XRD) pattern having one ormore peaks at about 4.3, 8.7, 12.9, 18.7 and 28.0±0.2° 2θ.

In another embodiment, the present invention provides lumacaftorForm-LA1 further characterized by X-Ray diffraction (XRD) pattern havingone or more peaks at about 4.3, 8.7, 12.9, 14.8, 17.5, 17.7, 18.7, 19.3,20.3, 21.8, 22.2, 22.8, 23.5, 23.6, 25.7, 26.4, 28.0, 29.8, 33.0, 36.9,38.2, 40.1 and 43.7±0.2° 2θ.

In another embodiment, the present invention provides lumacaftorForm-LA1 characterized by a differential scanning calorimetry (DSC)thermogram substantially in accordance with FIG. 2.

In another embodiment, the present invention provides lumacaftorForm-LA1 characterized by a thermo gravimetric analysis (TGA) curvesubstantially in accordance with FIG. 3.

In another embodiment, the present invention provides lumacaftorForm-LA1 characterized by X-Ray powder diffraction (XRD) patternsubstantially in accordance with FIG. 1, a differential scanningcalorimetry (DSC) thermogram substantially in accordance with FIG. 2 anda thermo gravimetric analysis (TGA) curve substantially in accordancewith FIG. 3.

In another embodiment, the present invention provides a process for thepreparation of lumacaftor Form-LA1, comprising:

-   -   a) dissolving lumacaftor in water and a suitable base at a        suitable temperature,    -   b) optionally, cooling the solution to less than 25° C., and    -   c) isolating the lumacaftor Form-LA1.

In another embodiment, the present invention provides a process for thepreparation of lumacaftor Form-LA1, comprising:

-   -   a) dissolving lumacaftor in water and a suitable base at a        suitable temperature,    -   b) optionally, cooling the solution to less than 25° C., and    -   c) isolating the lumacaftor Form-LA1; wherein the suitable base        is selected from the group comprising ammonium bases, alkali        metal hydroxides, alkali metal alkoxides, alkali metal        carbonates, alkali metal bicarbonates or organic bases and        mixture thereof.

As used herein, unless otherwise specified, lumacaftor, which is used asa starting material is known in the art and can be prepared by any knownmethods, for example lumacaftor may be synthesized as disclosed ininternational PCT publication WO2007/056341 or may be by following theprocess described in the present specification. The lumacaftor startingmaterial may be any crystalline or other form of lumacaftor, includingamorphous, various solvates, hydrates, salts and cocrystals as long aslumacaftor Form-LA1 is produced during the process of the invention orlumacaftor obtaining as existing solution from a previous processingstep.

The aforementioned step a) process includes dissolving lumacaftor inwater and a suitable base. The dissolution step may optionally furtherincludes first suspending lumacaftor in water and then adding a suitablebase or vice-versa and heating the resultant suspension at a suitabletemperature of about 35° C. to about reflux; preferably at about 50° C.to about 80° C. to form a clear solution.

The suitable base used herein for dissolving lumacaftor include but isnot limited to ammonium bases such as ammonium hydroxide, ammoniumcarbonate, ammonium bicarbonate and the like; alkali metal hydroxidessuch as lithium hydroxide, sodium hydroxide, potassium hydroxide and thelike; alkali metal alkoxides such as sodium methoxide, sodium ethoxide,sodium tert-butoxide, potassium tert-butoxide and the like; alkali metalcarbonates such as sodium carbonate, potassium carbonate, cesiumcarbonate and the like; alkali metal bicarbonates such as sodiumbicarbonate, potassium bicarbonate and the like; organic bases selectedfrom the group comprising of triethylamine, isopropyl ethylamine,diisopropyl amine, diisopropyl ethylamine and the like and mixturethereof; preferably the base used herein for dissolving lumacaftor isammonium hydroxide, sodium hydroxide, potassium tert-butoxide andmixtures thereof; more preferably ammonium hydroxide.

Step b) of the aforementioned process involves gradually cooling thesolution to less than 25° C.; preferably to about 10° C. to about 20°C., for sufficient period of time to precipitate out lumacaftor from thesolution, preferably for a period of about 30 min to 5 hours andisolating the lumacaftor Form-LA1 by known methods in the art, forexample filtration, decantation. Typically, if stirring is involved, thetemperature during stirring can range from about 10° C. to about 25° C.and the resultant product may optionally be further dried at atemperature of about 60° C. to about 75° C.

In a specific embodiment, the present invention provides a process forthe preparation of lumacaftor Form-LA1, comprising:

-   -   a) dissolving lumacaftor in water and ammonium hydroxide at a        temperature of about 35° C. to reflux temperature,    -   b) optionally, cooling the solution to less than 25° C., and    -   c) isolating the lumacaftor Form-LA1.

In another specific embodiment, the present invention provides a processfor the preparation of lumacaftor Form-LA1, comprising:

-   -   a) suspending lumacaftor in water,    -   b) adding ammonium hydroxide to the step a) suspension or        vice-versa,    -   c) heating the step b) reaction mixture to about 35° C. to        reflux temperature,    -   d) cooling the step c) reaction mixture to less than 25° C., and    -   e) isolating the lumacaftor Form-LA1.

The aforementioned step a) process includes dissolving lumacaftor inwater and ammonium hydroxide. The dissolution step may optionallyfurther includes first suspending lumacaftor in water and then adding aammonium hydroxide or vice-versa and heating the resultant suspension ata temperature of about 35° C. to about reflux temperature; preferably atabout 50° C. to about 80° C. to form a clear solution.

Step b) of the aforementioned process involves gradually cooling thesolution to about less than 25° C.; preferably to about 10° C. to about20° C., for sufficient period of time to precipitate out lumacaftor fromthe solution, preferably for a period of about 30 min to 5 hours andisolating the lumacaftor Form-LA1 by known methods in the art, forexample filtration, decantation. Typically, if stirring is involved, thetemperature during stirring can range from about 10° C. to about 25° C.and the resultant product may optionally be further dried at atemperature of about 60° C. to about 75° C.

In another embodiment, the present invention provides lumacaftorForm-LA1 prepared by the processes described above, is characterized byX-Ray diffraction (XRD) pattern having one or more peaks at about 4.3,8.7, 12.9, 14.8, 17.5, 17.7, 18.7, 19.3, 20.3, 21.8, 22.2, 22.8, 23.5,23.6, 25.7, 26.4, 28.0, 29.8, 33.0, 36.9, 38.2, 40.1 and 43.7±0.2° 2θ.

In another embodiment, the present invention provides lumacaftorForm-LA1 prepared by the processes described above, having a chemicalpurity of 98% or more as measured by HPLC, preferably 99% or more, morepreferably 99.5% or more.

In another embodiment, the present invention provides lumacaftorForm-LA2.

In another embodiment, the lumacaftor Form-LA2 of the present inventionis an ammonia solvate.

In another embodiment, the present invention provides lumacaftorForm-LA2 characterized by a powder X-ray diffraction (PXRD) patternsubstantially in accordance with FIG. 4.

In another embodiment, the present invention provides lumacaftorForm-LA2 characterized by X-Ray diffraction (XRD) pattern having one ormore peaks at about 3.9, 7.7, 11.6, 12.9, 13.8, 14.9, 15.6, 16.8, 17.4,17.9, 19.1, 19.5, 21.1, 21.7, 22.8, 23.4, 25.7, 26.4, 27.5, 29.2, 30.2,31.4, 32.7, 33.8, 35.3, 36.2, 37.4, 39.3 and 43.7±0.2° 2θ.

In another embodiment, the present invention provides lumacaftorForm-LA2 characterized by a differential scanning calorimetry (DSC)thermogram substantially in accordance with FIG. 5.

In another embodiment, the present invention provides lumacaftorForm-LA2 characterized by a thermo gravimetric analysis (TGA) curvesubstantially in accordance with FIG. 6.

In another embodiment, the present invention provides lumacaftorForm-LA2 characterized by X-Ray powder diffraction (XRD) patternsubstantially in accordance with FIG. 4, a differential scanningcalorimetry (DSC) thermogram substantially in accordance with FIG. 5 anda thermo gravimetric analysis (TGA) curve substantially in accordancewith FIG. 6.

In another embodiment, the present invention provides a process for thepreparation of lumacaftor Form-LA2, comprising: exposing lumacaftorForm-LA1 under ammonia atmosphere.

The aforementioned process of lumacaftor Form-LA2 includes exposinglumacaftor Form-LA1 under ammonia atmosphere at about 25° C. to about35° C. for a period of 10 to 30 hours.

In another embodiment, the present invention provides lumacaftorForm-LA3.

In another embodiment, the lumacaftor Form-LA3 of the present inventionis an anhydrous crystalline form.

In another embodiment, the present invention provides lumacaftorForm-LA3 characterized by a powder X-ray diffraction (PXRD) patternsubstantially in accordance with FIG. 7.

In another embodiment, the present invention provides lumacaftorForm-LA3 characterized by X-Ray diffraction (XRD) pattern having one ormore peaks at about 6.0, 8.3, 8.7, 9.2, 9.6, 10.0, 10.4, 11.0, 11.5,12.0, 12.5, 12.9, 13.3, 13.7, 14.9, 15.5, 15.8, 16.5, 16.8, 17.3, 17.9,18.4, 19.0, 19.4, 20.0, 20.6, 21.2, 21.7, 22.4, 23.3, 24.5, 25.1, 25.6,26.5, 27.9, 28.9 and 37.6±0.2° 2θ.

In another embodiment, the present invention provides lumacaftorForm-LA3 characterized by a differential scanning calorimetry (DSC)thermogram substantially in accordance with FIG. 8.

In another embodiment, the present invention provides lumacaftorForm-LA3 characterized by a thermo gravimetric analysis (TGA) curvesubstantially in accordance with FIG. 9.

In another embodiment, the present invention provides lumacaftorForm-LA3 characterized by X-Ray powder diffraction (XRD) patternsubstantially in accordance with FIG. 7, a differential scanningcalorimetry (DSC) thermogram substantially in accordance with FIG. 8 anda thermo gravimetric analysis (TGA) curve substantially in accordancewith FIG. 9.

In another embodiment, the present invention provides a process for thepreparation of lumacaftor Form-LA3, comprising: heating lumacaftorForm-LA1 at about 100° C. to about 140° C.; preferably at about 115° C.to about 125° C. for about 3 to 12 hours.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising at least one of the novel crystalline forms oflumacaftor described above and at least one or more pharmaceuticallyacceptable excipients.

In another embodiment, the novel crystalline forms of lumacaftor of thepresent invention may be used as an intermediate in the preparation ofother polymorphic forms of lumacaftor.

In another embodiment, the present invention provides an improvedprocess for the preparation of lumacaftor.

In another embodiment, the present invention provides an improvedprocess for the preparation of lumacaftor.

In another embodiment, the present invention provides an improvedprocess for the preparation of lumacaftor of Formula I,

comprising: reacting a compound of Formula II; wherein ‘X’ represent asuitable leaving group, with a compound of Formula III in presence of apalladium catalyst and base in a suitable solvent to obtain lumacaftor.

The starting materials, a compound of Formula II and Formula III isknown in the art and can be produced by methods known and recognized bythe organic chemist of ordinary skill in the art. For example, such aprocess is described in PCT publication No. WO2007/056341 which isincluded by reference herein in its entirety.

Generally, microwave support reactions are having many processlimitations such as specific equipments, high investment costs,uncontrolled reaction temperatures and pressure and unable to tracereaction progression on multi scale reactions, thereby not suitable forcommercial scale manufacturing. For example commercial microwaveirradiation reactions rapidly shoot-up power outputs, which increasesthe reaction internal temperature and pressure, which are uncontrollableat commercial level. Further, due to vigorous heating and microwave raysmost often involves formation of dark coloured residues which resultsnasty workup process and generally required tedious columnchromatographic purification, which are not suitable for commercialscale manufacturing process.

The '341 publication discloses a process for preparation of lumacaftor,which involves reaction of compound of Formula III (chloro intermediate)with a compound of Formula II by microwave irradiation at a temperatureof about 150° C. The use of special techniques such as reaction bymicrowave irradiation is not viable for commercial scale operations asthis technique involves specialized expensive equipments. The prolongedperiod of microwave irradiation at 150° C. leads to formation ofunwanted process impurities in higher levels. Also the disclosed processinvolves tedious reverse-phase preparative liquid chromatographicpurifications, which contributes significant impact on the final yieldand purity, makes the process not viable for large scale manufacturing.

To overcome the difficulties associated with the process describedabove, the inventors of the present invention have developed an improvedprocess for the preparation of lumacaftor with high product yield andquality and substantially free of impurities, which process replacescumbersome microwave irradiation with conventional synthesis method,thereby avoiding the formation of impurities.

The reaction of compound of Formula II; wherein ‘X’ represent a suitableleaving group, with a compound of Formula III is carried out in presenceof a palladium catalyst and base in a suitable solvent to obtainlumacaftor.

Unless otherwise specified the term “suitable leaving group” used hereinthe specification represents a halo group such as chloro, bromo, iodo;OTf (triflate); OTs (tosylate) and the like; preferably the leavinggroup is Cl or Br.

The palladium catalyst herein used includes, but is not limited totetrakis (triphenylphosphine) palladium(0), tetrakis(tri(otolyl)phosphine) palladium(0), tris(dibenzylideneacetone) dipalladium(0),[1,1′-bis(diphenylphosphino) ferrocene] dichloropalladium(II),palladium(II) acetate and the like and mixtures thereof; preferably thepalladium catalyst is tetrakis (triphenylphosphine) palladium(0).

The base used herein for the reaction of a compound of Formula II;wherein ‘X’ represent as above, with a compound of Formula III includebut is not limited to alkali metal hydroxides such as lithium hydroxide,sodium hydroxide, potassium hydroxide and the like; alkali metalalkoxides such as sodium methoxide, sodium ethoxide, sodiumtert-butoxide, potassium tert-butoxide and the like; alkali metalcarbonates such as sodium carbonate, potassium carbonate, cesiumcarbonate and the like; alkali metal bicarbonates such as sodiumbicarbonate, potassium bicarbonate and the like; and organic bases suchas triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropylethylamine, N-methyl morpholine, piperidine, pyridine and the like andtheir mixtures thereof; preferably the base is potassium carbonate,sodium methoxide and sodium tert-butoxide; more preferably the base ispotassium carbonate.

The suitable solvent for reaction of a compound of Formula II; wherein‘X’ represent as above, with a compound of Formula III include but isnot limit to ethers, amides, sulfoxides, aromatic hydrocarbons, waterand mixtures thereof. The ethers include, but are not limited totetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethylether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane,1,2-dimethoxy ethane, and the like; amides include, but are not limitedto dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone andthe like; sulfoxides include, but are not limited to dimethyl sulfoxideand the like; aromatic hydrocarbons include, but are not limited totoluene, xylene; water and the like and mixture thereof; preferably thesuitable solvent is dimethyl formamide, 1,4-dioxane and toluene; morepreferably the suitable solvent is dimethyl formamide.

The reaction of a compound of Formula II; wherein ‘X’ represent asabove, with a compound of Formula III is advantageously carried out at atemperature of about 25° C. to reflux temperature; preferably at about85° C. to about 105° C.

After completion of the reaction, the resultant reaction may be cooledto about 25° C. to about 35° C. Then water may be charged to thereaction mass and washed the reaction mass with a suitable waterimmiscible organic solvent such as toluene, ethyl acetate, methylenechloride and the like; preferably with toluene. Then the productcontaining aqueous layer again charged with a suitable water immiscibleorganic solvent such as toluene, ethyl acetate, methylene chloride andthe like; preferably with methylene chloride and then pH adjusted to4.5±0.5 with suitable acid such as hydrochloric acid, acetic acid andthe like. Then the product containing water immiscible organic solventmay be separated and evaporated under vacuum to obtain a residue. Thenthe residue may be dissolved in organic solvent such as methylenechloride at temperature of about 25° C. to about 45° C. and then coolingthe solution to about less than 20° C. to precipitate solid lumacaftor.The precipitated lumacaftor may be separated by methods known in theart, for example filtration.

In another embodiment, the above obtained lumacaftor may be used as anintermediate in the preparation of novel polymorphic forms of thepresent invention.

In another embodiment, the above obtained lumacaftor may be used as anintermediate in the preparation of lumacaftor Form-LA1, Form-LA2 orForm-LA3 of the present invention.

In another embodiment, the present invention provides a process for thepreparation of lumacaftor Form-LA1, comprising:

-   -   a) reacting a compound of Formula II; wherein ‘X’ represent a        suitable leaving group, with a compound of Formula III in        presence of a palladium catalyst and base in a suitable solvent        to obtain lumacaftor,    -   b) dissolving the lumacaftor of step a) in water and a suitable        base at a suitable temperature,    -   c) optionally, cooling the solution to less than 25° C., and    -   d) isolating the lumacaftor Form-LA1.

Preparation of Lumacaftor of step a) and its conversion to Lumacaftorform LA1 is carried out by the processes described as above of thepresent invention.

In another embodiment, the present invention provides lumacaftorprepared by the processes described above, having a chemical purity of98% or more as measured by HPLC, preferably 99% or more, more preferably99.5% or more.

In another embodiment, the present invention provides lumacaftorForm-LA1, Form-LA2 or Form-LA3 prepared by the processes describedabove, having a chemical purity of 98% or more as measured by HPLC,preferably 99% or more, more preferably 99.5% or more.

In another embodiment, the present invention provides the use of novelcrystalline forms of lumacaftor Form-LA1, Form-LA2 or Form-LA3 as anintermediate to prepare other polymorphic forms of lumacaftor.

In another embodiment, the present invention provides a process for thepreparation of lumacaftor Form I, comprising:

-   -   a) suspending lumacaftor Form-LA1 in a suitable solvent; and    -   b) isolating the lumacaftor Form I.

The Lumacaftor Form I is a known compound and is disclosed in theliterature, for example, disclosed in the U.S. Pat. No. 8,507,534.

The starting material of Lumacaftor Form-LA1 can be prepared accordingto the process of present invention described herein above.

The step a) of providing a suspension of lumacaftor Form-LA1 in asuitable solvent; preferably in water, may include heating the reactionmass to a temperature of about 50° C. to about reflux temperature,preferably to a temperature of about 65° C. to about 75° C.

The step b) of isolation of lumacaftor Form-I, may include cooling thereaction mass to a temperature of about 25-35° C. such that thelumacaftor Form-I can be precipitated from the reaction mass and can beisolated by conventional techniques such as filtration. The resultantwet product may optionally be further dried. Drying can be suitablycarried out in a tray dryer, vacuum oven, air oven, fluidized bed drier,spin flash dryer, flash dryer and the like.

Suitable pharmaceutical compositions are solid dosage forms, such astablets with immediate release or sustained release of the activeprinciple, effervescent tablets or dispersion tablets and capsules.Optionally, the pharmaceutical compositions of the invention may becombination products comprising one or more additional pharmaceuticallyactive components in addition to lumacaftor.

EXAMPLES

The following non limiting examples illustrate specific embodiments ofthe present invention. They are not intended to be limiting the scope ofthe present invention in any way.

Example 1 Preparation of Lumacaftor

Dimethyl formamide (500 mL), compound of Formula II (100 g; X=Br) andpotassium carbonate solution (162 g dissolved in 620 mL water) werecharged in a reaction flask at 25-35° C. To the reaction mass compoundof Formula III (48.4 g) and Pd(PPh₃)₄ (4.21 g) were charged at 25-35°C., heated to 85-95° C. and stirred for 1 hr at same temperature. Aftercompletion of the reaction, filtered the reaction mass and diluted thefilterate with toluene (300 mL) and water (700 mL) and stirred for 10min at 25-35° C. Then the product containing aqueous layer was separatedand charged methylene chloride (300 mL) to the aqueous layer. Reactionmass pH was adjusted to 4-5 with hydrochloric acid solution at 25-35° C.and stirred for 1 hr at same temperature. Then the product containingorganic layer was separated and concentrated at below 80° C. to obtain aresidue. The obtained residue was dissolved in methylene chloride (300mL) at 25-35° C. and stirred for 60 min at same temperature. Reactionmass was allowed to cool to 15-25° C. The solid was isolated byfiltration and washed with methylene chloride (100 mL) and dryed at50-55° C. to obtain lumacaftor. Yield: 95 gm.

Example 2: Preparation of Lumacaftor

Dimethyl formamide (700 mL), compound of Formula II (100 g; X=Cl) andFormula III (54.3 g) were charged in a reaction flask at 25-35° C. Tothe reaction mass added potassium carbonate solution (181 g dissolved in620 mL water) and Pd(PPh₃)₄ (4.7 g) were charged at 25-35° C., heated to100-105° C. and stirred for 1-3 hrs at same temperature. Aftercompletion of the reaction, reaction mass allowed to cool to 25-35° C.and charged water (700 ml) at same temperature. Reaction mass was washedwith toluene (2×300 mL). Then the product containing aqueous layer wasseparated and charged methylene chloride (500 mL) to the aqueous layer.Reaction mass pH was adjusted to 4-5 with hydrochloric acid solution at25-35° C. and stirred for 1 hr at same temperature. Then the productcontaining organic layer was separated and concentrated at atmosphericpressure up to 3-4 vol remains in the flask and strip off with toluene(2×100 mL) and methylene chloride (100 mL) at below 75° C. to obtain aresidue. The obtained residue was dissolved in methylene chloride (100mL) at 25-35° C. and stirred for 60 min at same temperature. Reactionmass was allowed to cool to 15-25° C. The solid was isolated byfiltration and washed with methylene chloride (100 mL) and dryed at50-55° C. to obtain lumacaftor. Yield: 110 gm.

Example 3 Preparation of Lumacaftor Form-LA1

Lumacaftor (100 g; from Ex-2), water (400 mL) and ammonium hydroxide (35mL) were added in to a round bottom flask at 25-35° C. Reaction mass washeated to 65-75° C. to obtain clear solution. Reaction mass was allowedto cool to 35-45° C. and stirred for 30-60 min at same temperature.Reaction mass was further allowed to cool to 15-25° C. and stirred for1-2 hrs at same temperature. The precipitated solid was isolated byfiltration and washed with water (2×100 mL) and dryed at 65-75° C. toobtain lumacaftor Form-LA1. Yield: 95 gm; Purity by HPLC—99.98%;PXRD—FIG. 1; DSC—FIG. 2 and TGA—FIG. 3.

Example 4 Preparation of Lumacaftor Form-LA2

Lumacaftor Form-LA1 (100 gms) was kept in a desiccator in a medium ofammonia solution (35 mL) for 24 hrs to obtain lumacaftor Form-LA2.Yield: 101 gm; Purity by HPLC—100%; PXRD—FIG. 4; DSC—FIG. 5 and TGA—FIG.6.

Example 5 Preparation of Lumacaftor Form-LA3

Lumacaftor Form-LA1 (100 gms) was dryed in vacuum oven at 115-125° C.for 6 hrs to obtain lumacaftor Form-LA3. Yield: 99 gm; Purity byHPLC—99.93%; PXRD—FIG. 7; DSC—FIG. 8 and TGA—FIG. 9.

Example 6

Preparation of Lumacaftor Form-I from Lumacaftor Form-LA1:

Lumacaftor Form-LA1 (1 g) and water were added into a round bottom flaskat 25-35° C. The temperature of the reaction mass was raised to 65-75°C. and maintained for 3-5 hrs. The solution was gradually cool to 20-30°C., filtered and dried at 60° C. to obtain Lumacaftor Form-I. Yield: 0.9g; HPLC purity 99.96%.

It will be understood that various modifications may be made to theembodiments disclosed herein. Therefore the above description should notbe constructed as limiting, but merely as exemplifications of preferredembodiments. For example, the functions described above and implementedas the best mode for operating the present invention are forillustration purposes only. Other arrangements and methods may beimplemented by those skilled in the art without departing from the scopeand spirit of this invention. Moreover, those skilled in the art willenvision other modifications within the scope and spirit of thespecification appended hereto.

1. Lumacaftor Form-LA1 characterized by X-Ray diffraction (XRD) patternhaving one or more peaks at about 4.3, 8.7, 12.9, 14.8, 17.5, 17.7,18.7, 19.3, 20.3, 21.8, 22.2, 22.8, 23.5, 23.6, 25.7, 26.4, 28.0, 29.8,33.0, 36.9, 38.2, 40.1 and 43.7±0.2° 2θ.
 2. Lumacaftor Form-LA1 of claim1, further characterized by a powder X-ray diffraction (PXRD) patternsubstantially in accordance with FIG.
 1. 3. Lumacaftor Form-LA1 of claim1, further characterized by differential scanning calorimetry (DSC)thermogram substantially in accordance with FIG.
 2. 4. LumacaftorForm-LA1 of claim 1, further characterized by thermo gravimetricanalysis (TGA) curve substantially in accordance with FIG.
 3. 5.Lumacaftor Form-LA1 of claim 1, further characterized by differentialscanning calorimetry (DSC) thermogram substantially in accordance withFIG. 2 and a thermo gravimetric analysis (TGA) curve substantially inaccordance with FIG.
 3. 6. A process for the preparation of lumacaftorForm-LA1, comprising: a) dissolving lumacaftor in water and a base at asuitable temperature, b) optionally, cooling the solution to less than25° C., and c) isolating the lumacaftor Form-LA1.
 7. The process ofclaim 6, wherein the base is selected from one or more of the groupconsisting of ammonium bases, alkali metal hydroxides, alkali metalalkoxides, alkali metal bicarbonates, organic bases and or mixturethereof.
 8. The process of claim 7, wherein the base is ammoniumhydroxide, ammonium carbonate, ammonium bicarbonate, lithium hydroxide,sodium hydroxide, potassium hydroxide, sodium methoxide, sodiumethoxide, sodium tert-butoxide, potassium tert-butoxide, sodiumcarbonate, potassium carbonate, cesium carbonate, sodium bicarbonate,potassium bicarbonate, triethylamine, isopropyl ethylamine, diisopropylamine, diisopropyl ethylamine, or mixture thereof.
 9. The process ofclaim 8, wherein the base is ammonium hydroxide.
 10. The process ofclaim 6, wherein the step a) is carried out at a temperature of about50° C. to about 80° C. 11-24. (canceled)
 25. An improved process for thepreparation of lumacaftor of Formula I,

comprising: reacting a compound of Formula II with a compound of FormulaIII in the presence of a palladium catalyst and a base in a solvent toobtain the lumacaftor, wherein ‘X’ represent a leaving group.


26. The process of claim 25, wherein the leaving group is selected fromone of the group consisting of chloro, bromo, iodo, triflate ortosylate.
 27. The process of claim 26, wherein the leaving group ischloro or bromo.
 28. The process of claim 25, wherein the palladiumcatalyst is selected from one of the group consisting of tetrakis(triphenylphosphine) palladium(0),tetrakis(tri(otolyl)phosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0),[1,1′-bis(diphenyl phosphino) ferrocene]dichloropalladium (II) or palladium(II) acetate.
 29. The process ofclaim 25, wherein the base is selected from the group consisting oflithium hydroxide, sodium hydroxide, potassium hydroxide, sodiummethoxide, sodium ethoxide, sodium tert-butoxide, potassiumtert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate,sodium bicarbonate, potassium bicarbonate, triethylamine, isopropylethylamine, diisopropyl amine, diisopropyl ethylamine, N-methylmorpholine, piperidine, or pyridine.
 30. The process of claim 25,wherein the solvent is selected from the group consisting oftetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethylether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane,1,2-dimethoxy ethane, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidinone, dimethyl sulfoxide, toluene, xylene water, or mixturethereof.
 31. The process of claim 25, wherein the palladium catalyst istetrakis (triphenylphosphine) palladium(0); the base is potassiumcarbonate; and the solvent is dimethyl formamide.
 32. The process ofclaim 25, wherein the reaction is carried out at a temperature of about85° C. to about 105° C. 33-44. (canceled)
 45. A process for thepreparation of lumacaftor Form I, comprising: a) suspending lumacaftorForm-LA1 in a solvent; and b) isolating the lumacaftor Form I.
 46. Theprocess of claim 45, wherein the solvent is water.
 47. The process ofclaim 45, wherein the step a) is carried out at a temperature of about65° C. to about 75° C.
 48. A pharmaceutical composition comprising:lumacaftor according to claim 1; and at least one pharmaceuticallyacceptable excipient.